A major direction in the laboratory is to establish the relevance of glycosylation abnormalities to clinical diagnosis, particularly in identifying premalignant cellular changes and in differentiating malignant from nonmalignant disease. Extrapolating from our results in the rat AFP model, glycosylation is abnormal very early in the hepatocarcinogenic exposure before the serum AFP concentration is significantly elevated, long before the process becomes irreversible, and while prevention of progression to malignancy may be possible. In collaborations with investigators in Boston, MA, Richmond, VA, Washington, DC, Rochester, NY, West Africa, and the Solomon Islands, we are following both hepatitis B virus-positive and -negative patients with chronic nonmalignant liver disease, in addition to patients following liver transplantation, for early evidence of neoplastic transformation as reflected in abnormal AFP glycosylation patterns. Hereditary tyrosinemia presently is the best model for a premalignant liver condition which almost invariably progresses to malignancy. In collaboration with Belanger in Quebec, we will be monitoring AFP glycosylation heterogeneity serially in patients initially less than 2 years old with tyrosinemia but no evidence of tumor. Other tumor markers share the same lack of specificity for malignancy as AFP. We have found that serum alpha-1 acid glycoprotein shows a glycosylation pattern characteristic of hepatocellular carcinoma which is not seen in the protein from normal subjects or from patients with chronic active hepatitis, Crohn's disease, or normal pregnancy. (M)